Protocolized Care for Early Septic Shock (ProCESS)

• Changes in markers of inflammation, oxidative stress, cellular hypoxia and coagulation/thrombosis. [ Time Frame: study hour 0, 6, 24 & 72 ] [ Designated as safety issue: No ]
• Resource use and costs of alternative resuscitation strategies [ Time Frame: at discharge or 60 days, whichever comes first ] [ Designated as safety issue: No ]

• Changes in markers of inflammation, oxidative stress, cellular hypoxia and coagulation/thrombosis. [ Time Frame: study hour 0, 6, 24 & 72 ]
• Resource use and costs of alternative resuscitation strategies [ Time Frame: length of hospitalization ]

The ProCESS study is large, 5-year, multicenter study of alternative resuscitation strategies for septic shock. The study hypothesizes that there are "golden hours" in the initial management of septic shock where prompt, rigorous, standardized care can improve clinical outcomes.

Septic shock is a condition of acute organ dysfunction due to severe infection, with a mortality of up to 50%. Current efforts to improve care are limited by little practical evidence regarding the interventions in and timing of sepsis therapies. ProCESS is a prospective, randomized, three-arm parallel-group trial of alternative resuscitation strategies for early septic shock. The study objective is to improve the management of septic shock by exploring the clinical, biological, and economic aspects of alternative resuscitation strategies. This will be done by comparing two alternative resuscitation strategies to usual care in subjects with septic shock.

Comparisons:

1. Early Goal Directed Therapy (EGDT) - The subjects' blood pressure and blood oxygen levels will be monitored via the insertion of a central venous catheter (CVC). The study team will use this information to give fluid, blood and heart medications in a structured fashion. The central venous catheter to be used in this plan is FDA approved and routinely used in hospitals.
2. Protocolized Standard Care (PSC) - The subjects' blood pressure and blood oxygen levels will be monitored with standard equipment (without the CVC). The study team will use this information to prescribe fluid and heart medications in a structured fashion. CVCs will only be used when standard IVs cannot give the proper amount of fluids and medicines. Blood transfusions will be given according to currently recommended guidelines.
3. Usual Care (UC) - Subjects will be treated according to their attending physician's standard treatment plan and without any influence from the study team.

The primary hypotheses to be tested sequentially are that: protocolized resuscitation (EGDT and PSC) results in lower hospital mortality than usual care and Early Goal Directed Therapy results in lower hospital mortality than Protocolized Standard Care. These hypotheses will be tested on all enrolled subjects.

The study is powered to find an absolute mortality reduction (ARR) of ~6-7%. Based on the control arm mortality rate, we originally estimated a sample size of 1950. During the trial, the ProCESS Coordinating Center monitored the overall mortality rate, and appreciated that it was markedly lower than originally projected. Therefore, following a series of new calculations, in February 2013, the trial was re-sized to 1350 patients (450 patients per arm). The new size preserves the same power to find the same ARR. The resizing was fully blinded and approved by the NIH.

• Sepsis
• Severe Sepsis
• Septic Shock

• Procedure: Early Goal Directed Therapy (EGDT)
  Subjects will have a CVC inserted for continuous monitoring of their CVP and Scv02. Early structured treatment will be provided based on subjects' CVP, mean arterial pressure (MAP) and Scv02 measurements.
• Procedure: Protocolized Standard Care (PSC)
  Routine equipment will be used to monitor subjects' blood pressure and oxygen levels. Early structured treatment is based on the subjects' systolic blood pressure and the study doctors' judgment of fluid status and perfusion status.
• Procedure: Usual Care (UC)
  Attending physicians will provide routine care to subjects. Study measurements and treatments will be based on the physicians'/sites' standard practices.

• Experimental: 1
  Early Goal Directed Therapy (EGDT) - The study team will insert a central venous catheter (CVC) for continuous monitoring of the subjects' central venous pressure (CVP) and central venous oxygen saturation (Scv02). The study team will use this information to give fluid, blood, and heart medications in a structured fashion. The CVC is FDA approved and routinely used in hospitals.
  Intervention: Procedure: Early Goal Directed Therapy (EGDT)
• Experimental: 2
  Protocolized Standard Care (PSC)- The study team will monitor the subjects' blood pressure and blood oxygen level with routine equipment. The study team will use this information to give fluid and heart medications in a structured fashion. CVCs will only be used when standard IVs are unable to give the proper amount of fluids and medicines. Blood transfusions will be given according to currently recommended guidelines.
  Intervention: Procedure: Protocolized Standard Care (PSC)
• Active Comparator: 3
  Usual Care - The attending physicians will treat the subjects according to their standard treatment plan and without any influence from the study team. A member of the study team will simply observe and record what happens.
  Intervention: Procedure: Usual Care (UC)

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Inclusion criteria:

• At least 18 years of age
• Suspected infection

• Two or more systemic inflammatory response syndrome (SIRS) criteria

  • Temperature </= 36˚ C or >/= 38˚C
  • Heart rate >/= 90 beats per minute
  • Mechanical ventilation for acute respiratory process or respiratory rate >/= 20 breaths per minute or PaC02 < 32 mmHg
  • WBC >/= 12,000/mm³ OR </= 4,000/mm³ OR > 10% bands
• Refractory hypotension (a systolic blood pressure < 90 mm Hg despite an IV fluid challenge of at least 1,000 mLs over a 30 minute period) or evidence of hypoperfusion (a blood lactate concentration >/= 4 mmol/L)

Exclusion criteria:

• Known pregnancy
• Primary diagnosis of acute cerebral vascular event, acute coronary syndrome, acute pulmonary edema, status asthmaticus, major cardiac arrhythmia, active gastrointestinal hemorrhage, seizure, drug overdose, burn or trauma
• Requirement for immediate surgery
• ANC < 500/mm³
• CD4 < 50/mm³
• Do-not-resuscitate status
• Advanced directives restricting implementation of the protocol
• Contraindication to central venous catheterization
• Contradiction to blood transfusion (e.g., Jehovah's Witness)
• Treating physician deems aggressive care unsuitable
• Participation in another interventional study
• Transferred from another in-hospital setting